HSV-1 Hijacks Mitophagy Pathway to Drive Brain Inflammation — Taurine Fights Back

Herpes simplex encephalitis (HSE), caused by HSV-1, is the most common form of viral encephalitis and carries high mortality and lasting neurological damage even with current antiviral drugs like acyclovir. Understanding how HSV-1 manipulates host cell biology to evade immune defenses is critical for developing better therapies.

This study systematically investigated how HSV-1 affects mitophagy—the selective autophagy pathway that clears damaged mitochondria—in neuronal and microglial cells and in a mouse HSE model. Using transmission electron microscopy, Western blot, RT-qPCR, flow cytometry, and ELISA, the researchers showed that HSV-1 infection initially triggers mitophagy early in infection but subsequently suppresses it at later stages, causing accumulation of dysfunctional mitochondria both in vitro and in the brain tissue of infected mice.

Mechanistically, the team identified two HSV-1 proteins, ICP34.5 and US11, as key suppressors of the EIF2S1 (eIF2α)-ATF4 transcriptional axis. Under normal stress conditions, phosphorylation of EIF2S1 activates ATF4, which transcriptionally drives PRKN expression to sustain mitophagy. Both ICP34.5 and US11 block EIF2S1 phosphorylation, thereby preventing ATF4 activation and reducing PRKN mRNA levels. The consequent loss of PRKN-dependent mitophagy allows damaged mitochondria to persist, releasing signals that amplify NF-κB-mediated neuroinflammation.

Functionally, inhibiting mitophagy with the specific inhibitor Mdivi-1 worsened HSV-1 infection, while restoring it via PRKN overexpression or chemical agonists (CCCP, rotenone) significantly reduced viral titers and inflammatory cytokine production. PRKN-overexpressing mice showed markedly improved survival, reduced brain pathology, less eye damage, and attenuated neurodegeneration after HSV-1 challenge compared to wild-type animals.

Notably, taurine—a gut microbial metabolite found to be differentially regulated during HSV-1 infection—emerged as a natural mitophagy activator. Taurine transcriptionally upregulated PRKN expression, stimulated mitophagy, and inhibited HSV-1 replication and NF-κB neuroinflammation both in cell culture and in the mouse HSE model. These findings position mitophagy activation, particularly through the PRKN pathway, as a viable therapeutic target for HSV-1-associated neurological disease, complementary to existing antiviral drugs.